Method for local heating by means of magnetic particles

ABSTRACT

The invention relates to a method as well as to a system for the local heating of a target region of an object by varying the magnetization of magnetic or magnetizable substances. A magnetic field is then generated whose magnetic field strength varies in space in such a manner that a first sub-region ( 301 ) of low magnetic field strength and a second sub-region ( 302 ) which encloses the first sub-region and has a higher magnetic field strength are formed in the target region. Subsequently, the position in space of the two sub-regions in the target region is varied with a given frequency for so long that the particles are heated to a desired temperature due to frequent variation of the magnetization.

The invention relates to a method and a system for the local heating ofregions of an object by variation of the magnetization of magnetic ormagnetizable substances.

Methods and systems of this kind are known, for example, from themedical field. In the course of so-called hyperthermia andthermo-ablation operations, diseased tissue is heated to giventemperatures so that the tissue mortifies or is destroyed.

A problem generally encountered in hyperthermia consists in thataccurately localized and above all homogeneous heating of a region ofinterest of the body can usually be achieved only with difficulty oronly by making a large expenditure on specific hardware. In order toconfine the hyperthermia to diseased tissue as well as possible, it isparticularly important to confine the heating to the region to betreated.

The publication DE 19937492 discloses a magnetic field applicator forthe heating of magnetic or magnetizable substances or solid bodies inparts of an object. The arrangement consists of a magnetic yoke which ismade of ferrite components and comprises pole shoes as well as coilswound around the pole shoes. Between the pole shoes there is formed areceiving space in which the object to be treated is to be positioned.The entire receiving space, and hence the entire part of the objectsituated therein, is traversed by a magnetic alternating field duringoperation.

It is an object of the invention to provide a method and a system forthe heating of an adjustable target region of an object.

This object is achieved by means of a method for the heating of magneticparticles which are present in a target region, which method includesthe steps of

-   a) generating a magnetic field whose magnetic field strength varies    in space in such a manner that a first sub-region having a low    magnetic field strength and a second sub-region having a higher    magnetic field strength are formed in the target region,-   b) changing the position in space of the two sub-regions in the    target region for so long and with such a frequency that the target    region is heated.

The method in conformity with the invention utilizes magnetic particleswhich are present in the target region to be heated in the object.Because of its internal structure, the object may permanently containsuch particles. Alternatively, such particles can be introduced into theobject, for example, by way of a liquid, prior to the heating.

A spatially inhomogeneous magnetic field is generated in the targetregion. The magnetic field in the first sub-region is so weak that themagnetization of the particles is not saturated. Under the influence ofa magnetic field having a given field strength, magnetic particles arenot saturated when the magnetization of the particles changes inresponse to an increase of the field strength of the magnetic field.This first sub-region is preferably a spatially coherent region; it maybe a punctiform region but also a line, a surface or a volume. In thesecond sub-region (that is, in the part of the target region whichremains outside the first sub-region) the magnetic field is strongenough to keep the particles in a state of saturation. Under theinfluence of a magnetic field, magnetic particles are saturated if thechange of their magnetization in response to an increase of the magneticfield strength is clearly less in comparison with the response in thenon-saturated state.

The state of saturation is dependent on the type of magnetic particlesused and is generally imposed by their physical structure or solid statestructure. The magnetization is saturated, for example, when themagnetization of practically all particles is oriented approximately inthe direction of the external magnetic field (second sub-region), sothat in response to a further increase of the magnetic field themagnetization at that area increases significantly less than in thefirst sub-region in response to a corresponding increase of the magneticfield. For other magnetic particles the state of saturation is reachedwhen the respective magnetization is oriented in the direction of theexternal magnetic field for a predominant number of inner magneticregions.

When the position in space of the first sub-region is changed slightly,the magnetization changes of those particles which are situated in thefirst sub-region or which migrate from the first to the secondsub-region or vice versa. Because of this change of the magnetization,heat losses occur, for example, due to known hysteresis effects orhysteresis-like effects in the particles or due to the initiation ofparticle movements, and the temperature of the medium surrounding theparticles is heated in a heating region. When the first sub-region ofthe magnetic field is shifted through the entire target region, theheating region will correspond to the target region. The smaller thefirst sub-region, the smaller the size of the smallest possible heatingregion will be.

Because only a comparatively small amount of heat is produced when themagnetization is changed only once, the magnetization must be changedseveral times. The necessary number of changes, that is, the frequencywithin a given time interval, and the associated temperature rise of themedium surrounding the particles in the heating region is dependent onthe particle concentration, on the production of heat per change (whichitself is dependent on the particle structure and the speed of themagnetic reversal), and the dissipation of heat in the regionssurrounding the heating region.

Further advantages over methods which are known from the state of theart result from the use of two sub-regions with different magneticfields, where the first sub-region with a low field strength is situatedwithin the second sub-region with a higher field strength and themagnetic field of the second sub-region traverses the entire targetregion. When the target region constitutes a small part of an object,the magnetic field of the second sub-region can also traverse regions ofthe object which surround the target region or the entire object. Theshift of the first sub-region which is necessary for the heating thentakes place exclusively within the target region, so that even thoughthe field strength of the magnetic field of the first sub-region changesin the regions outside the target region, the magnetization of theparticles does not change. It is thus advantageously achieved that theregions surrounding the target region are not heated, because themagnetic particles present therein are in the saturated state. Moreover,it is not necessary either to position the magnetic particlesexclusively in the target region in order to avoid heating ofsurrounding regions. This is advantageous for medical applications inwhich the magnetic particles reach, for example, the target region viathe blood stream and hence are also present in the surrounding regions.

As a result of a small size of the first sub-region it can be achievedthat an almost arbitrarily shaped target region can be heated by way ofa grid-like variation of the position in space of the first sub-region.The smaller the first sub-region, the finer the gridding may be andhence the more arbitrary the shape of the region of interest may alsobe. Furthermore, the target region can be subdivided into varioussub-regions, each of which receives a different amount of heat. When thesub-regions consist of similar materials, they will be heated to adifferent extent. When the sub-regions consist of different materials,the entire target region can be practically homogeneously heated byspecific adaptation of the respective heating of the sub-regions. Tothis end, for example, the frequency or the duration of the heating ofthe relative sub-regions can be adapted. Alternatively, in order toachieve more effective heating, the target region can deliberately beheated inhomogeneously (for example, outer regions stronger than innerregions).

One possibility for changing the position in space of the twosub-regions consists in displacing a coil system and/or a permanentmagnet system (or parts thereof) for generating the magnetic field onthe one hand or the object with the region to be heated on the otherhand relative to one another. This is a preferred method when very smallobjects are treated by means of very strong gradients and the frequencyrequired for heating is low. Claim 2, however, describes a preferredembodiment which does not require mechanical movements. The position inspace of the two sub-regions can then be changed comparatively quickly;this offers additional advantages in the production of heat and enableshigh frequencies.

Magnetic particles that are suitable for the method in conformity withthe invention should have dimensions which are small in comparison withthe size of the regions to be heated by means of the method inaccordance with the invention. Furthermore, the magnetization of theparticles should reach the saturated state in response to as low aspossible field strengths of the magnetic field. The lower the fieldstrength required for this purpose, the less the heating per change ofthe magnetization will be, but the higher the spatial resolution will beor the weaker the (external) magnetic field to be generated in thetarget region has to be. When the method is used for medicalexaminations, moreover, it is important that the particles are nottoxic.

In the embodiment disclosed in claim 3 the particles are so small thatonly a single magnetic domain (monodomain) can be formed within such aparticle or that no Weiss regions can arise. The dimensions of theparticles should then be in the nanometer range. Particles of this kindare used, for example, in contrast media for MR (=magnetic resonance)examinations. Such particles have a size of from 5 to 10 nm. When thedimensions of the particles are larger, smaller field strengths maysuffice to ensure saturation of the magnetization of the particles.However, the dimensions should not be so large that a plurality ofmagnetic domains or Weiss regions can be formed in the particles. Forparticles known at present, therefore, suitable particle sizes are in arange of from 2 nm to approximately 800 nm, the upper limit also beingdependent on the material. A material that is suitable for monodomainparticles is, for example, magnetite (Fe₃O₄). The indication of theparticle size is given merely by way of example, since the materialproperties are more important in this context.

The embodiment disclosed in claim 4, however, utilizes larger particlesin which a number of magnetic domains may be formed. With a view to thespatial resolution, these particles should consist of a magneticmaterial which enters the saturated state in response to a low magneticfield strength (implying a low saturation induction). This condition canbe dispensed with in the further embodiment disclosed in claim 5.Because the particles then comprise only a thin layer of a magneticmaterial, magnetic saturation is ensured at a low field strength even ifthe layer does not consist of a material having a low saturationinduction.

The embodiment disclosed in claim 6 enables the particles to be appliedin a simple manner in the case of medical examination. When use is madeof a dispersion with the monodomain particles in conformity with claim3, this dispersion can be injected into the blood stream so as toachieve a concentration of particles in the tissue to be heated. Suchdispersions are not toxic and are known to be used for contemporarymagnetic hyperthermia methods and thermo-ablation methods as well as forthe previously mentioned contrast enhancement in MR methods. In the caseof MR methods the particles are so small (from 5 to 10 nm) that no Weissregions can be formed therein.

A dispersion with the particles defined in claim 4 or 5 can be used, forexample, after a patient to be examined has orally taken thisdispersion, for the heating of selected regions of the gastrointestinaltract or, for example, by injection into the blood stream or directlyinto the tissue to be treated, for the heating of tumor tissue.

Generally speaking, it is advantageous when the particles have a loweffective anisotropy (in this context and hereinafter the term“effective anisotropy” is to be understood to mean the magneticanisotropy resulting from the shape anisotropy and from the crystalanisotropy), because a change of their magnetization direction does notrequire a rotation of these particles, so that quickly changing magneticfields can also be used. However, in the embodiment disclosed in claim 6use is made of the fact that in the case of particles having asufficiently large effective anisotropy (for example, elongateparticles) a change of the magnetization direction implies a mechanicalrotation of the particles which can also be used for the generating ofheat.

The heat released when the magnetization of the magnetic particles isfrequently changed is due to various effects. In the case of particleswith a plurality of Weiss regions heat is produced in known manner bythe hysteresis effect where Weiss regions are directed, againstmolecular forces, out of the natural states of equilibrium. Thecontribution per magnetizable unit of volume is then proportional to thesurface area enclosed by the hysteresis loop when the flux density isplotted as a function of the field strength of the magnetic field. Thegeneration of heat can be attributed to other effects, that is,so-called hysteresis-like effects, notably in the case of smallparticles with a monodomain. As opposed to the previously mentionedhysteresis effects, such hysteris-like effects usually occur only in thecase of rapidly changing magnetic fields.

It is to be noted that nowadays a large number of magnetic particles ofdifferent shapes are known; their shape may be independent from theheating mechanisms. In addition to spherical particles there are, forexample, needle-shaped particles which usually comprise a plurality ofmagnetic domains and exhibit a pronounced mechanical rotation under theinfluence of a magnetic field for alignment. Furthermore, flat,lens-shaped particles are known in which the magnetization can rotatewithin one plane only. For further shapes in this respect reference ismade to relevant technical literature.

An embodiment as disclosed in claim 7 imparts special adhesionproperties to the magnetic particles, so that a very specificconcentration in space of the particles is stimulated notably in specialtissues.

The kind of particle in conformity with claim 8 is particularlyadvantageous in order to avoid excessive heating of the target region.When the temperature of a magnetic particle exceeds the Curietemperature, the magnetization of the particle no longer changes despitea correspondingly changing magnetic field. Consequently, these particlesdo not produce heat. When the temperature drops below the Curietemperature again, the particle responds once more to the magnetic fieldand heat is produced again. With a view to the respective planned use,the Curie temperature can be taken into account already for theselection of the materials for the particles. This is of importance, forexample, for hyperthermia where diseased tissue is heated totemperatures beyond 41° C., but where excessive heating should beavoided because, for example, surrounding, healthy tissue would also bedamaged by transfer of heat. In the case of thermo-ablation temperaturesbeyond 47° C. are pursued for acute cell destruction, but in this caseexcessive temperatures again lead to detrimental side effects.

An arrangement for carrying out the method in accordance with theinvention is disclosed in claim 9. In conformity with claim 10 agradient field can be generated by means of permanent magnets. In theregion between two poles of the same polarity there is formed aninhomogeneous magnetic field which comprises a small first sub-region oflow field strength which is surrounded by a second sub-region of higherfield strength. The magnetization is not saturated only for theparticles which are present in the region around the zero point of thefield (first sub-region). The magnetization is in the state ofsaturation for the particles outside this region.

In order to make the gradient field switchable, in conformity with claim11 there is provided a gradient coil system for generating a gradientfield in the target region which is similar to the previously describedmagnetic field. If the gradient coil system comprises, for example, twosimilar windings which are situated to both sides of the target regionbut are traversed by opposed currents (Maxwell coil), this magneticfield is zero at a point on the winding axis and increases substantiallylinearly with an opposed polarity to both sides of this point. In thefurther embodiment in accordance with claim 12 the region produced bythe gradient coil arrangement around the zero point of the field, thatis, the first sub-region, is shifted within the target region by thetemporally variable magnetic field. When the variation in time and theorientation of this magnetic field are suitably chosen, the zero pointof the field can traverse the entire target region in this manner.

The local heating will be faster as the frequency at which the positionof the zero point of the field in the target region is changed ishigher, that is, the faster the temporally variable magnetic fieldsuperposed on the magnetic gradient field changes. However, from atechnical point of view it is difficult to generate a temporallyvariable magnetic field whose amplitude suffices to shift the zero pointof the field to each point of the target region on the one hand andwhose frequency of change is high enough to produce fast heating on theother hand. This problem is mitigated by the embodiment disclosed inclaim 13 in which three magnetic fields which are variable at adifferent speed and with a different amplitude are generated, that is,preferably by means of three coil arrangements. It is a furtheradvantage that the frequencies of the field variations may be so fast(for example, >20 kHz) that they are beyond the limits of human hearingand hence the additional burden on a patient is reduced. The furtherembodiment disclosed in claim 14 enables the displacement of thefield-free point in a three-dimensional region.

Thus far examples were taken from the medical field so as to illustratethe invention. However, generally speaking, it is also possible to usethe method in accordance with the invention wherever magnetic particlescan be introduced into regions of an object to be heated and the objectcan be treated by means of magnetic fields.

The invention will be described in detail hereinafter with reference todrawings. Therein:

FIG. 1 shows an apparatus for carrying out the method in accordance withthe invention,

FIG. 2 shows the field line pattern produced by one of the coilsincluded therein,

FIG. 3 shows a magnetic particle present in the target region,

FIGS. 4 a to 4 c show the magnetization characteristics of suchparticles,

FIGS. 4 d and 4 e show the field strength dependent heating of givenparticles and their positions in the magnetic field,

FIG. 5 shows a circuit diagram of the apparatus shown in FIG. 1, and

FIG. 6 shows the shift of the field-free point in a two-dimensionalregion.

The reference numeral 1 in FIG. 1 denotes an object, in this case beinga patient, who is arranged on a patient table, only part of the top 2 ofwhich is shown. Prior to a treatment of, for example, a tumor, a liquidwith magnetic particles is injected into the patient 1.

FIG. 3 shows a particle of this kind. It comprises a spherical substrate100, for example, of glass which is provided with a soft-magnetic layer101 which has a thickness of, for example, 5 nm and consists, forexample, of an iron-nickel alloy (for example, Permalloy). This layermay be covered, for example, by means of a coating layer 102 whichprotects the particle against acids. The strength of the magnetic fieldrequired for the saturation of the magnetization of such particles isdependent on the diameter of the particles. In the case of a diameter of10 μm, a magnetic field of approximately 800 A/m (correspondingapproximately to a flux density of 1 mT) is then required, whereas inthe case of a diameter of 100 μm a magnetic field of 80 A/m suffices.Even smaller values are obtained when a coating of a material having alower saturation magnetization is chosen or when the layer thickness isreduced.

FIGS. 4 a and 4 b show the magnetization characteristic, that is, thevariation of the magnetization M as a function of the field strength H,in a dispersion with such particles. It appears that the magnetization Mno longer changes beyond a field strength +H_(C) and below a fieldstrength −H_(C), which means that a saturated magnetization is involved.The magnetization is not saturated between the values +H_(C) and −H_(C).

FIG. 4 a illustrates the effect of a sinusoidal magnetic field H(t) ifno further magnetic field is active. The magnetization reciprocatesbetween its saturation values at the rhythm of the frequency of themagnetic field H(t). The resultant variation in time of themagnetization is denoted by the reference M(t) in FIG. 4 a. It appearsthat the magnetization also changes periodically and that themagnetization of such a particle is periodically reversed.

The dashed part of the line at the center of the curve denotes theapproximate mean variation of the magnetization as a function of thefield strength. As a deviation from this center line, the magnetizationextends slightly to the right when the magnetic field H increases from−H_(C) to +H_(C) and slightly to the left when the magnetic field Hdecreases from +H_(C) to −H_(C). This known effect is called ahysteresis effect which underlies a mechanism for the generation ofheat. The hysteresis surface area which is formed between the paths ofthe curve and whose shape and size are dependent on the material, is ameasure for the generation of heat upon variation of the magnetization.

FIG. 4 b shows the effect of a sinusoidal magnetic field H(t) on which astatic magnetic field H₁ is superposed. Because the magnetization is inthe saturated state, it is practically not influenced by the sinusoidalmagnetic field H(t). The magnetization M(t) remains constant in time atthis area. Consequently, the magnetic field H(t) does not cause a changeof the state of the magnetization and does not give rise to heat. Thehysteresis curve is not shown herein.

Above and below the patient 1 or the table top there is provided aplurality of pairs of coils whose range defines the region of treatment(FIG. 1). A first coil pair 3 comprises the two identically constructedwindings 3 a and 3 b which are arranged coaxially above and below thepatient and which are traversed by equal currents, be it in opposeddirections. Preferably, direct currents are used in this case. Thegradient magnetic field thus generated is represented by the field lines300 in FIG. 2. It has a substantially constant gradient in the directionof the (vertical) axis of the coil pair and reaches the value zero in apoint on this axis. Starting from this field-free point, the strength ofthe magnetic field increases in all three spatial directions as thedistance increases. In a region 301 which is denoted by a dashed line(the first sub-region) around the field-free point the field strength isso small that the magnetization of particles present at that area is notsaturated, whereas it is in a state of saturation outside the region301. In the region remaining outside the region 301 (the secondsub-region 302) the magnetization of the particles is in the state ofsaturation.

The size of the region 301 is dependent on the one hand on the strengthof the gradient of the gradient magnetic field and on the other hand onthe strength of the magnetic field required for saturation. The fieldstrength of this magnetic field amounts to, for example, 800 A/m for adiameter of 10 μm of the sphere shown in FIG. 3 and to 80 A/m for adiameter of 100 μm. For the latter value and a gradient of the fieldstrength of the magnetic field amounting to 160·10³ A/m² the region 301in which the magnetization of the particles is not saturated hasdimensions of 1 mm.

When a further magnetic field is superposed on the gradient magneticfield in the region of treatment, the region 301 is shifted in thedirection of this magnetic field; the extent of this shift increases asthe strength of the magnetic field increases. When the superposedmagnetic field is variable in time, the position of the region 301varies accordingly in time and in space.

In order to generate these temporally variable magnetic fields for anydirection in space there are provided three further coil pairs. The coilpair 4 with the windings 4 a and 4 b generates a magnetic field whichextends in the direction of the coil axis of the coil pair 3 a, 3 b,that is, vertically. To this end the two windings are traversed by equalcurrents in the same direction. The effect that can be achieved by meansof this coil pair can in principle also be achieved by the superpositionof currents in the same direction on the opposed, equal currents in thecoil pair 3 a, 3 b, so that the current decreases in one coil pair andincreases in the other coil pair. However, it may be advantageous whenthe temporally constant gradient magnetic field and the temporallyvariable vertical magnetic field are generated by separate coil pairs.

Two further coil pairs, comprising the windings 5 a, 5 b and 6 a, 6 b,are provided in order to generate magnetic fields which extendhorizontally in space in the longitudinal direction of the patient andin a direction perpendicular thereto. If coil pairs of the Helmholtztype, like the coil pairs 3 a, 3 b and 4 a, 4 b, were used for thispurpose, these coil pairs would have to be arranged to the left and theright of the region of treatment or in front of and behind this region,respectively. This would affect the accessibility of the region oftreatment.

Therefore, the windings 5 a, 5 b and 6 a, 6 b of the coil pairs are alsoarranged above and below the region of treatment and, therefore, theirwinding configuration must be different from that of the coil pair 4 a,4 b. Coils of this kind, however, are known from the field of magneticresonance apparatus with open magnets (open MRI) in which an RF coilpair is situated above and below the region of treatment, said RF coilpair being capable of generating a horizontal, temporally variablemagnetic field. Therefore, the construction of such coils need not befurther elaborated herein.

As an alternative for the coil pair 3 shown in FIG. 1, permanent magnetscan also be used to generate the gradient magnetic field. In the spacebetween two poles of permanent magnets there is formed a magnetic fieldwhich is similar to that of FIG. 2, that is, when the poles have thesame polarity.

FIG. 5 shows a circuit diagram of the apparatus shown in FIG. 1. Thediagrammatically represented coil pair 3 (the indices a, b have beenomitted for the sake of simplicity for all coil pairs in FIG. 5)receives a direct current from a controllable current source 31, whichcurrent can be controlled and switched on and off by the control unit10. The control unit 10 co-operates with a workstation 12 via which auser can operate the apparatus and via which the apparatus can beconnected to a network of further computers. Depending on itscapabilities, the control unit 10 or other components of the apparatusmay also be integrated in the workstation 12. User input is possible viaa keyboard or another input device 14.

The coil pairs 4, 5, 6 receive their currents from current amplifiers41, 51 and 61. The variation in time of the currents Ix, Iy and Iz to beamplified, producing the desired magnetic fields, is imposed by arespective waveform generator 42, 52 and 62, respectively. The waveformgenerators 42, 52, 62 are controlled by the control unit 10 whichcalculates the variation in time of the currents required for therelevant treatment and loads it into the waveform generators. During thetreatment these signals are read from the waveform generators andapplied to the amplifiers 41, 51, 61 which form the currents requiredfor the coil pairs 4, 5 and 6 therefrom.

For particles which contribute to the heating due to mechanical motion,a value of, for example,

$130\mspace{20mu}\frac{{Hz}\mspace{14mu} m}{A}$can be used as a target value for the frequency of the magnetic fieldvariation (for the particles shown in FIG. 3, for example, frequenciesof

$25\mspace{20mu}\frac{{kHz}\mspace{14mu} m}{A}\mspace{14mu}{or}\mspace{14mu} 250\mspace{20mu}\frac{{kHz}\mspace{14mu} m}{A}$can be used in dependence on the layer properties), so that a frequencyof approximately 1 MHz is obtained for a field strength of the magneticfield of

${8 \cdot 10^{3}}\mspace{14mu}\frac{A}{m}$as required for complete magnetic reversal. This frequency is imposed onone of the three coil pairs 4, 5 or 6, for example, the coil pair 4, sothat the target region is influenced by an alternating field and themagnetic field region 301 is continuously shifted in a rapidlyoscillating fashion in the direction of the magnetic field of the coilpair 4. As a result, a quasi-one-dimensional region of a length whichcan be adjusted by way of the amplitude of the corresponding coilcurrent is heated as a target region in the treatment region (in thecase of a spherical shape of the region 301, an elongate cylindricalregion is obtained instead of the strip). The total heating powerapplied to this strip is dependent inter alia also on the frequency andthe amplitude of the alternating field (given by the length in space ofthe strip), as well as on the field strength required for the maximumdevelopment of heat (for example, saturation field strength). The higherthe frequency, the higher the heating power will be. The rapidlyoscillating magnetic field region 301 is moved in the other dimension bymeans of the other two coil pairs 5 and 6, so that the entire targetregion is heated.

FIG. 6 shows the superposition of the individual magnetic fields by wayof example. The region 301 is shifted rapidly in the y direction in anoscillating fashion, the shift being due to the periodically varyingmagnetic field of the coil pair 4. For a better representation, thefrequency of the magnetic field generated by the coil pair 4 is shown tobe significantly lower, that is, in comparison with the frequencies ofthe other field, than is actually the case in practice.

The field of the coil pair 5 which varies comparatively slowly incomparison with the field in the y direction is superposed on this fieldin the x direction. When a given position is reached in the x direction,the shift in the x direction is reversed (the region 301 is thus shiftedbackwards), and at the same time the field in the y direction is variedby a constant amount, so that the two-dimensional shift of the region301 through the target region as shown in FIG. 7 is obtained as the partof the treatment region to be heated. If the constant amount issignificantly smaller, only a small shift of the field will occur in they direction, so that because of overlaps the region 301 will cover apoint in the target region repeatedly. If a further component issuperposed on this field after each scan of the two-dimensional region,that is, a component which shifts the magnetic field in the z direction(corresponding to the magnetic field of the coil pair 6), the region 301can be shifted through a three-dimensional target region.

Generally speaking, a non-linear relationship exists between the shiftof the region 301 from its position at the center of the gradient coilarrangement 3 and the current through the gradient coil arrangement.Moreover, all three coils must generally generate a magnetic field ifthe region 301 is to be shifted along a straight line extending outsidethe center (for example, in the case of a grid-like shift through thetarget region). The foregoing is taken into account by the control unitin selecting the variation in time of the currents, for example, bymeans of appropriate tables. Therefore, the region 301 can be shiftedalong arbitrarily formed paths through the examination zone, so that theabove displacement of a rapidly oscillating strip is to be consideredmerely as an example.

For given applications it may be useful to heat only a punctiform orspherical region instead of a one-dimensional strip and to displace thispunctiform region in all three spatial directions. This can be realized,for example, by means of a fifth coil pair which is not shown in theFigures and which shifts the first sub-region 301 in a rapidlyoscillating fashion in space exactly so far that practically onlyparticles which are located in and around the sub-region 301 contributeto the heating. Alternatively, a corresponding alternating field canalso be generated by one or more of the coil pairs 4, 5 or 6, at thesame time corresponding, slowly varying magnetic fields being superposedfor the displacement in space of the sub-region 301. The configurationin space and in time of the rapid oscillation is dependent on theparticles used.

Furthermore, the temperature of the target region can be determinedduring the treatment by means of components which are not shown. Thiscan be realized, for example, by means of a temperature sensor which isintroduced into the target region prior to the treatment. Alternatively,known microwave methods can also be used. In order to preventoverheating, the frequency can be dynamically adapted during theheating, that is, in dependence on the measured temperature. Forexample, in order to slow down the temperature rise the frequency isdecreased more and more as the temperature increases. If no means fortemperature measurement are used, the parameters concerning frequencyand duration are selected on the basis of the user's experience.

Instead of using the magnetic particles with a soft-magnetic coating asdescribed with reference to FIG. 3, so-called monodomain particles of aferromagnetic material or a ferrimagnetic material can be used. Theseparticles have dimensions in the nanometer range and are so small thatno magnetic domains or Weiss regions can be formed therein. Suchparticles can be injected into the blood stream of a patient in asuitable colloidal dispersion. Dispersions of this kind are alreadyinjected as a contrast medium in the field of magnetic resonanceimaging. The magnetic particles used in that field have a size of from 5to 10 nm. The magnetic field strength required for the saturationdecreases by 1/d³, where d is the particle diameter. Therefore, thedimensions of these particles should be as large as possible, but not solarge that magnetic domains can be formed therein. Depending on therelevant magnetic material, the optimum value is between 2 and 800 nm.

FIG. 4 c shows an example of the variation of the magnetization of sucha particle in the case of a slowly varying magnetic field H. As opposedto the particles shown in FIG. 3, in this case no hysteresis loop isformed, or only a very small one. However, if the magnetic field Hvaries rapidly, heat is produced due to the previously mentionedhysteresis-like effects, for example, due to the Néel rotation (dampedspin dynamics as well as anisotropies in the molecular composition), dueto the rotation of the particles in the surrounding medium or due to theferromagnetic resonance. Because these effects are known, they will notbe elaborated herein and reference is made to the relevant technicalliterature.

In given types of such particles a particularly large amount of heat isproduced when the magnetic field is not varied in the entire rangebetween the two field strengths −H_(C) and +H_(C) required forsaturation, but only in a small range. FIG. 4 d shows, by way ofexample, the amount of heat A generated in dependence on the magneticfield H for such a particle, on each field strength H there beingadditionally superposed a rapidly oscillating alternating field H(t) ofan amount ΔH which is very small in comparison with the field strengthH, so that an overall field amounting to H=H_(const)±ΔH is obtained. Incomparison with H_(const), the field strength ΔH is so small that itcannot be depicted in FIG. 4 d. In FIG. 4 d the generating of heat isthe greatest in the case of a field strength H=H₂±ΔH under the influenceof the alternating field ΔH. In addition to the amplitude, the selectionof the frequency of the alternating field ΔH is dependent to a highdegree on the composition of the particles and may range from a fewhundred Hz to as far as the microwave range.

It follows therefrom that when the first sub-region is shifted, aparticle of this kind generates most heat when the region of the firstsub-region, having the field strength H₂, traverses the particle. Forthe purpose of illustration FIG. 4 e shows the gradient field of FIG. 2with the first sub-region 301. The line 305 characterizes a region withthe field strength H₂. When the region 301 is shifted only very littlein space and in a rapidly oscillating fashion around the co-ordinatezero point shown, an alternating field is superposed (notably on theregion with the field strength H₂) and the particles located in thevicinity off or on the line 305 produce most heat. The particles locatedremotely within the line 305 then hardly contribute to the generation ofheat, because the field strength H in the region is smaller than H₂ andonly little heat is produced for such a field strength in conformitywith FIG. 4 d. In this case the configuration of the magnetic fieldwithin the line 305 is of secondary importance only and, as opposed tothe situation shown, the field strength need not absolutely necessarilybecome zero. In dependence on the path traveled during the rapid shiftin space and/or on the hysteresis-like effect causing the development ofheat, it may occur that the particles contributing to the heating arenot located in a coherent sub-region around the line 305 as shown inFIG. 4 e, but in a plurality of sub-regions of the first sub-region 301which are separated from one another.

For magnetic particles it is to be noted that they become concentratedto a different degree in different types of tissue. This effect can beused for specific positioning of the magnetic particles and hence forthe local heating and can be intensified by enclosing the particles bymeans of a coating of organic molecules which enhance thebio-compatibility and have given adhesion properties so as to beconcentrated on or in given biological structures. In the ideal case theconcentration of the particles takes place only in the parts of thetissue to be treated, so that on the one hand the risk of accidentalheating of neighboring parts of the tissue is reduced and on the otherhand the requirements as regards the precision of the shift in space ofthe first sub-region are mitigated.

The heating of the target region beyond a maximum temperature can beavoided when the magnetic material of the particles has a Curietemperature which is in the vicinity of the maximum permissibletemperature. In the case of a temperature increase beyond the Curietemperature, the particles lose their magnetic properties, so that noreversal of the magnetization takes place in response to variation ofthe magnetic field and hence no further heating occurs. When thetemperature drops below the Curie temperature again, the particles canbe magnetized once more.

Similar effects, which can also be used for temperature control, can beobserved for some ferromagnetic materials. When a so-called “comparisontemperature” is reached, the magnetic field strength required forsaturation drops to approximately the value zero. When this value isslightly exceeded, the necessary field strength immediately increasesagain. Temperature-dependent variations of the anisotropies of somemagnetic particles can also be suitably used for temperature control.

1. A method for the heating of magnetic particles which are present in atarget region, which method includes the steps of a) generating amagnetic field whose magnetic field strength varies in space in such amanner that a first sub-region (301) having a low magnetic fieldstrength and a second sub-region (302) having a higher magnetic fieldstrength are formed in the target region, b) changing the position inspace of the two sub-regions in the target region in a nonrotationalmanner for so long and with such a frequency that the target region isheated.
 2. A method as claimed in claim 1, in which a spatially andtemporally variable magnetic field is generated in order to change theposition in space of the two sub-regions in the target region.
 3. Amethod as claimed in claim 1, further comprising providing said magneticparticles as monodomain particles of a ferromagnetic material or aferrimagnetic material.
 4. A method as claimed in claim 1, furthercomprising providing said magnetic particles as multidomain particles ofa ferromagnetic material or a ferrimagnetic material.
 5. A method asclaimed in claim 4, further comprising providing substrates which havedimensions in the μm range and providing a layer of a ferromagnetic softmaterial which is thin in comparison with said dimensions as multidomainparticles on said substrates.
 6. A method as claimed in claim 3, furthercomprising providing said monodomain particles in a colloidaldispersion.
 7. A method as claimed in claim 1, further comprisingenclosing particles in a molecular envelope for tissue-specificconcentration.
 8. A method as claimed in claim 1, further comprisingheating the particles such that the temperature prevailing in the targetregion after the desired heating or the a maximum permissibletemperature in the target region corresponds to the Curie temperature.9. An arrangement for the heating of magnetic particles which arepresent in a target region, the arrangement comprising a) means forgenerating a magnetic field whose magnetic field strength varies inspace in such a manner that a first sub-region (301) having a lowmagnetic field strength and a second sub-region (302) having a highermagnetic field strength are formed in the target region, b) means forchanging the position in space of the two sub-regions in the targetregion in a nonrotational manner for so long and at such a frequencythat the target region is heated.
 10. An arrangement as claimed in claim9, in which the means for generating the magnetic field include apermanent magnet arrangement for generating a magnetic gradient fieldwhose direction is reversed in the first sub-region of the target regionand which comprises a zero-crossing.
 11. An arrangement as claimed inclaim 9, in which the means for generating the magnetic field includinga gradient coil system for generating a magnetic gradient field whosedirection is reversed in the first sub-region of the target region andwhich comprises a zero-crossing.
 12. An arrangement as claimed in claim9, comprising means for generating a magnetic field which is superposedon the magnetic gradient field and which varies in time in order toshift the two sub-regions in the target region.
 13. An arrangement asclaimed in claim 9, comprising means for generating a first magneticfield and at least two further magnetic fields which are superposed onthe magnetic gradient field, the first magnetic field being variablemore rapidly in time and with a lower amplitude whereas the two furthermagnetic fields are variable more slowly in time and with a higheramplitude.
 14. An arrangement as claimed in claim 13, in which the threemagnetic fields extend essentially perpendicularly to one another in thetarget region.